Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada; Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada; Division of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
Biochim Biophys Acta Mol Basis Dis. 2022 Nov 1;1868(11):166507. doi: 10.1016/j.bbadis.2022.166507. Epub 2022 Jul 25.
Sepsis is a life-threatening condition of organ dysfunction caused by dysregulated inflammation which predisposes patients to developing cardiovascular disease. The ketone β-hydroxybutyrate is reported to be cardioprotective in cardiovascular disease and this may be due to their signaling properties that contribute to reducing inflammation. While exogenous ketone esters (KE) increase blood ketone levels, it remains unknown whether KEs can reduce the enhanced inflammatory response and multi-organ dysfunction that is observed in sepsis. Thus, this study assesses whether a recently developed and clinically safe KE can effectively improve the inflammatory response and organ dysfunction in sepsis.
To assess the anti-inflammatory effects of a KE, we utilized a model of lipopolysaccharide (LPS)-induced sepsis in which an enhanced inflammatory response results in multi-organ dysfunction. Oral administration of KE for three days prior to LPS-injection significantly protected mice against the profound systemic inflammation compared to their vehicle-treated counterparts. In assessing organ dysfunction, KE protected mice from sepsis-induced cardiac dysfunction as well as renal dysfunction and fibrosis. Furthermore, KE administration attenuated the sepsis-induced inflammation in the heart, kidney, and liver. Moreover, these protective effects occurred independent of changes to enzymes involved in ketone metabolism.
These data show that the use of an exogenous KE attenuates the dysregulated systemic and organ inflammation as well as organ dysfunction in a model of severe inflammation. We postulate that this exogenous KE is an appealing and promising approach to capitalize on the protective anti-inflammatory effects of ketones in sepsis and/or other inflammatory responses.
败血症是一种由炎症失调引起的危及生命的器官功能障碍疾病，使患者易患心血管疾病。据报道，酮体β-羟丁酸在心血管疾病中有心脏保护作用，这可能是由于其信号特性有助于减少炎症。虽然外源性酮酯（KE）能增加血液中的酮水平，但目前尚不清楚 KE 是否能减轻败血症中观察到的增强的炎症反应和多器官功能障碍。因此，本研究评估了一种最近开发的、临床安全的 KE 是否能有效改善败血症中的炎症反应和器官功能障碍。
为了评估 KE 的抗炎作用，我们利用脂多糖（LPS）诱导的败血症模型，其中增强的炎症反应导致多器官功能障碍。与对照组相比，在 LPS 注射前三天口服 KE 治疗能显著保护小鼠免受严重的全身炎症。在评估器官功能障碍时，KE 能保护小鼠免受败血症引起的心脏功能障碍以及肾功能障碍和纤维化。此外，KE 治疗还能减轻败血症引起的心脏、肾脏和肝脏炎症。此外，这些保护作用的发生与酮代谢相关酶的变化无关。
这些数据表明，使用外源性 KE 能减轻严重炎症模型中失调的全身和器官炎症以及器官功能障碍。我们推测，这种外源性 KE 是一种有吸引力和有前途的方法，可以利用酮在败血症和/或其他炎症反应中的保护性抗炎作用。
